FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment
©2023 The Authors; Published by the American Association for Cancer Research..
Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cancer immunology research - 12(2024), 3 vom: 04. März, Seite 322-333 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Knorr, David A [VerfasserIn] |
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| Links: |
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| Themen: |
CTLA-4 Antigen |
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| Anmerkungen: |
Date Completed 06.03.2024 Date Revised 14.03.2024 published: Print UpdateOf: bioRxiv. 2023 Jan 20;:. - PMID 36711504 Citation Status MEDLINE |
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| doi: |
10.1158/2326-6066.CIR-23-0389 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366379828 |
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| 520 | |a Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Blanchard, Lucas |e verfasserin |4 aut | |
| 700 | 1 | |a Leidner, Rom S |e verfasserin |4 aut | |
| 700 | 1 | |a Jensen, Shawn M |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Ballesteros-Merino, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Bell, Richard B |e verfasserin |4 aut | |
| 700 | 1 | |a Baez, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Marino, Alessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Sprott, David |e verfasserin |4 aut | |
| 700 | 1 | |a Bifulco, Carlo B |e verfasserin |4 aut | |
| 700 | 1 | |a Piening, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Dahan, Rony |e verfasserin |4 aut | |
| 700 | 1 | |a Osorio, Juan C |e verfasserin |4 aut | |
| 700 | 1 | |a Fox, Bernard A |e verfasserin |4 aut | |
| 700 | 1 | |a Ravetch, Jeffrey V |e verfasserin |4 aut | |
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